Relative importance of four functional measures as predictors of 15-year mortality in the older Dutch population.

BACKGROUND: Decreased physical function is known to raise mortality risk. Little is known about how different physical function measures compare in predicting mortality risk in older men and women. The objective of this study was to compare four, objective and self-reported, physical function measures in predicting 15-year mortality risk in older men and women. METHODS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a population-based sample of the older Dutch population, sampled from municipal records. The 1995-96 cycle, including 727 men and 778 women aged 65-88 years, was considered as the baseline. Mortality was followed up through September 1, 2011. Physical function measures were: lower-body performance (chair stands test, walk test and tandem stand); handgrip strength (grip strength dynamometer); lung function (peak expiratory flow rate); functional limitations (self-report of difficulties in performing six activities of daily living). Cox proportional hazard models were used to determine the predictive value of each physical function measure for 15-year mortality risk, adjusted for demographic, lifestyle and health variables as potential confounders. RESULTS: 1031 participants (68.5%) had died. After adjustments for confounders, in models assessing single functional measures, peak flow was the strongest predictor of all-cause mortality in men (HR 1.76, CI 1.38-2.26, CI) and lower-body performance in women (HR 1.97,CI 1.40-2.76, CI). In a model including all four functional measures only peak flow was statistically significant in predicting mortality in both genders (men HR 1.54,CI 1.18-2.01 and women HR 1.45,CI 1.08-1.94). In women, lower-body performance (HR 1.66, CI 1.15-2.41) followed by grip strength (HR 1.38, CI 1.02-1.89), and in men, functional limitations (HR 1.43, CI 1.14-1.8) were the other significant predictors of all-cause mortality. CONCLUSION: Both objective and self-reported measures of physical functioning predicted all-cause mortality in a representative sample of the older Dutch population to different extents in men and women. Peak flow contributed important unique predictive value for mortality in both men and women. In women, however, lower-body performance tests had better predictive ability. A second-best predictor in men was self-reported functional limitations. Peak flow, and possibly one of the other measures, may be used in clinical practice for assessment in the context of time constraints.

Vitamin D supplementation and testosterone concentrations in male human subjects.

OBJECTIVE: A possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DESIGN: To investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). METHODS: In study 1, 92 subjects were randomized to either vitamin D (2000 IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6 weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200 IU daily) or placebo. Blood was drawn at baseline, after 8 and 16 weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. RESULTS: Serum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36 nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 0.5 and 0 nmol/l in studies 1, 2 and 3, respectively). CONCLUSIONS: In this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations.

Osteocalcin as a predictor of the metabolic syndrome in older persons: a population-based study.

BACKGROUND: Recent evidence indicates that the osteoblast-derived protein osteocalcin is able to influence adiposity and glucose homeostasis in mice. Little is known about this relationship in humans. OBJECTIVE: To investigate the association of plasma osteocalcin levels with the metabolic syndrome in a community-dwelling cohort of older persons in the Netherlands. DESIGN AND PARTICIPANTS: Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing multidisciplinary cohort study in a representative sample of the older Dutch population (≥65 years old). A total of 1284 subjects (629 men and 655 women) between the age of 65 and 88 years participated in this study. MEASUREMENTS: Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components were assessed as well as plasma osteocalcin levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 37·1%. The median osteocalcin level was 2·0 nmol/l. Plasma osteocalcin was inversely associated with the metabolic syndrome. The odds ratio (OR) was 3·68 with 95% confidence interval (CI) 2·53-5·34 for the lowest osteocalcin quartile compared to the highest quartile. The association between osteocalcin and the metabolic syndrome was mainly determined by high triglycerides, low HDL, waist circumference and hypertension. CONCLUSION: Low plasma osteocalcin levels are strongly associated with the metabolic syndrome in an older community-dwelling population.

Serum 25-hydroxyvitamin D levels and the metabolic syndrome in older persons: a population-based study.

BACKGROUND: Recent evidence indicates that a lower plasma level of 25-hydroxyvitamin D (25 OHD) is associated with a higher risk of the metabolic syndrome. It has not been studied in older people with a high prevalence of vitamin D insufficiency. OBJECTIVE: This study investigates the association between vitamin D status and the metabolic syndrome in community-dwelling older persons in the Netherlands. DESIGN AND PATIENTS: The study is part of the Longitudinal Aging Study Amsterdam, an ongoing cohort study in a representative sample of Dutch older persons. A total of 1286 subjects (629 men and 657 women) between the ages of 65 and 88 years participated in the study. MEASUREMENTS: Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components were assessed as well as serum 25 OHD levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 37·0%. The mean 25 OHD level was 53·3 nM; 47·8% had 25 OHD levels below 50 nM. There was a significantly increased risk of the metabolic syndrome in the subjects with serum 25 OHD levels below 50 nM, compared with that of subjects with levels over 50 nM [odds ratio (OR) = 1·54; 95% confidence interval (CI) 1·23-1·94]. After adjustment for confounders, age, sex, season, years of education, alcohol use, total activity, smoking and PTH, the OR was 1·29 (95% CI 1·00-1·68). The association between vitamin D deficiency and the metabolic syndrome was mainly determined by the components low HDL and (high) waist circumference. CONCLUSIONS: Vitamin D deficiency is common in the older population in the Netherlands, and subjects with serum 25 OHD below 50 nM have a higher risk of the metabolic syndrome.

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

INTRODUCTION: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. METHODS: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6134; Pre-results.

Salivary cortisol in the diagnosis of adrenal insufficiency: cost efficient and patient friendly.

Saliva as a diagnostic tool is patient friendly and offers analytical advantages. Hormonal analysis of saliva is not influenced by changes in concentrations of binding globulins as the free concentration of the hormones is measured. Analysis of salivary cortisol is common practice in the diagnostic work-up of hypercortisolism. We investigated the potential role of measuring salivary cortisol when adrenal insufficiency (AI) is suspected, to reduce the numbers of ACTH stimulation tests. Over a period of 6 years, patients undergoing an ACTH stimulation test (tetracosactide, 250 µg) in our hospital were included. Plasma cortisol (Elecsys, Cobas, Roche Diagnostics) and salivary cortisol and cortisone (LC-MS/MS) were determined at t = 0, 30 and 60 min after stimulation. Based on peak plasma cortisol levels, AI was ruled out in 113 patients and was established in 16 patients. Patients without AI displayed maximal salivary cortisol concentrations of 12.6-123.4 nmol/L (95th percentile) after stimulation, as opposed to 0.5-15.2 nmol/L in AI patients. At t = 0 min, a minimal salivary cortisol concentration of 1.0 nmol/L was observed in patients without AI, whereas AI patients had a maximum concentration of 5.9 nmol/L. Using these cut-off values, 34% of the initial patient group could be diagnosed without an ACTH stimulation test (28% >5.9 nmol/L, 6% <1.0 nmol/L). A novel diagnostic algorithm, including early morning salivary cortisol analysis can reduce the numbers of ACTH stimulation tests in patients suspected of AI. This patient-friendly method can thereby reduce total health care costs.

The interrelation between FGF23 and glucose metabolism in humans.

AIMS: Different studies point to a link between glucose metabolism and Fibroblast Growth Factor 23 (FGF23), an osteocyte-derived phosphaturic hormone. We aimed to investigate in humans the effect of (I) a glucose load and (II) a hyperinsulinemic-euglycemic clamp on FGF23 concentrations and conversely (III) the effect of a diet-induced increase in FGF23 concentration on glucose and insulin concentrations. METHODS: Plasma cFGF23 concentrations were measured during: I. an oral glucose tolerance test in eight adults with impaired glucose tolerance and vitamin D deficiency and II. a hyperinsulinemic-euglycemic clamp in nine healthy adults. III. Serum glucose and insulin concentrations were measured in nine healthy adults receiving a single-day phosphate-enriched or -restricted diet. RESULTS: I. A glucose load decreased FGF23 and phosphate concentrations. II. The hyperinsulinemic-euglycemic clamp decreased phosphate concentrations, but did not affect FGF23 concentrations. III. Fasting insulin and glucose concentrations remained unchanged after a diet-induced increase in FGF23 concentration. CONCLUSIONS: An oral glucose load in vitamin D deficient patients with impaired glucose metabolism decreased FGF23 concentrations, which cannot be attributed to changes in insulin concentration. Thus, bone may react rapidly after glucose loading by alternating FGF23 secretion. A diet-induced increase in FGF23 concentrations did not affect fasting glucose or insulin levels.

Vitamin D and type 2 diabetes.

Vitamin D deficiency is associated with a decreased insulin release, insulin resistance and type 2 diabetes in experimental and epidemiological studies. Animal studies show that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) stimulates the pancreatic ß-cell to secrete insulin. The relationship between vitamin D deficiency and insulin resistance could develop through inflammation, as vitamin D deficiency is associated with increased inflammatory markers. In addition, genetic polymorphisms of vitamin D -related genes may predispose to impaired glycemic control and type 2 diabetes. Epidemiologic studies showed an association between low serum 25-hydroxyvitamin D3 (25(OH)D3) concentration and an increased risk for the metabolic syndrome and type 2 diabetes. This may be partly explained by an increased fat mass. A possible causal relationship between vitamin D deficiency and type 2 diabetes should be proven by randomized clinical trials showing that either type 2 diabetes can be prevented or insulin release and insulin sensitivity can be improved by vitamin D supplements. The results of randomized clinical trials on the effect of vitamin D versus placebo, sometimes combined with calcium, in patients with impaired glucose tolerance ("prediabetes") or type 2 diabetes are inconsistent. Some studies showed a slight decrease of fasting plasma glucose or improvement of insulin resistance, but often only in posthoc analyses. These effects are mainly visible in patients with vitamin D deficiency and impaired glucose tolerance at baseline. Meta-analyses of randomized clinical trials in general did not show significant effects of vitamin D supplementation on glycemic control. Currently, several large scale randomized clinical trials with vitamin D supplementation in doses of 1600-4000IU/d are ongoing with glycemic control or incidence of diabetes mellitus as outcome. Vitamin D deficiency needs to be prevented or cured, but until the results of these trials are published, high-dose vitamin D supplementation cannot be recommended for prevention or amelioration of type 2 diabetes.

Effect of vitamin D supplementation on physical performance and activity in non-western immigrants.

Vitamin D deficiency is highly prevalent among non-western immigrants in The Netherlands and associated with poor physical performance. The aim of this study was to assess the effect of vitamin D supplementation on physical performance, exercise capacity, and daily physical activity in vitamin D-deficient, overweight non-western immigrants. A randomized double-blind, placebo-controlled trial was conducted to assess the effect of vitamin D on physical performance. A total of 130 participants were included. Eligibility criteria included overweight (BMI >27 kg/m(2)), 25-hydroxy vitamin D (25(OH)D) ≤50 nmol/l, and an age range of 20-65 years. The intervention group received 1200 IU vitamin D3 daily for 4 months; the control group received placebo. Both groups received 500 mg calcium daily. Outcome measures included physical performance (physical performance score), exercise capacity (a 6-min walk test (6-MWT)), and daily physical activity (questionnaire and accelerometer). There was no significant effect on physical performance, exercise capacity, or physical activity in the intention to treat analysis. In an explorative post hoc analysis restricted to participants reaching a serum 25(OH)D concentration of >60 nmol/l after intervention, there was an improvement of 19 m in the 6-MWT compared with the control group (P=0.053). Moderate dose vitamin D supplementation did not significantly improve physical performance, exercise capacity, or physical activity. However, when 25(OH)D concentrations reached >60 nmol/l after intervention, there was a borderline significant improvement in exercise capacity. Although the clinical relevance is not clear, this is a promising result, as all participants were overweight and did not improve their overall activity levels.

Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial.

BACKGROUND: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance, the metabolic syndrome, and type 2 diabetes. Because many non-Western immigrants in the Netherlands are vitamin D deficient, obese, and at high risk of diabetes, vitamin D supplementation may contribute to prevent diabetes and insulin resistance. OBJECTIVE: We examined the effect of vitamin D supplementation on insulin sensitivity and ß cell function in overweight, vitamin D-deficient, non-Western immigrants at high risk of diabetes. DESIGN: The study was a 16-wk, randomized, placebo-controlled trial. A total of 130 non-Western immigrants with prediabetes (fasting glucose concentration >5.5 mmol/L or random glucose concentration from 7.8 to 11.1 mmol/L) and vitamin D deficiency (serum 25[OH]D concentration <50 nmol/L) were randomly assigned after stratification by sex to receive either cholecalciferol (1200 IU/d) or a placebo for 16 wk. All participants received 500 mg Ca/d as calcium carbonate. The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment. Secondary outcomes were insulin-sensitivity variables, ß cell-function variables, and metabolic syndrome. RESULTS: Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups. After 4 mo of therapy, the mean between-group difference was 38 nmol/L (95% CI: 32.1, 43.9 nmol/L; P < 0.001). There was no significant effect on insulin sensitivity and ß cell function. In a post hoc analysis, when patients with diabetes at baseline were excluded, a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L (P = 0.040). CONCLUSIONS: Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or ß cell function or change the incidence of metabolic syndrome. However, after the exclusion of diabetic subjects, an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827.

Serum IGF1, metabolic syndrome, and incident cardiovascular disease in older people: a population-based study.

OBJECTIVE: High as well as low levels of IGF1 have been associated with cardiovascular diseases (CVD). The relationship of IGF1 with (components of) the metabolic syndrome could help to clarify this controversy. The aims of this study were: i) to investigate the association of IGF1 concentration with prevalent (components of) the metabolic syndrome; and ii) to examine the role of (components of) the metabolic syndrome in the relationship between IGF1 and incident CVD during 11 years of follow-up. METHODS: Data were used from the Longitudinal Aging Study Amsterdam, a cohort study in a representative sample of the Dutch older population (≥65 years). Data were available in 1258 subjects. Metabolic syndrome was determined using the definition of the US National Cholesterol Education Program Adult Treatment Panel III. CVD were ascertained by self-reports and mortality data. RESULTS: Levels of IGF1 in the fourth quintile were associated with prevalent metabolic syndrome compared with the lowest quintile (odds ratio: 1.59, 95% confidence interval (CI) 1.09-2.33). The middle up to the highest quintile of IGF1 was positively associated with high triglycerides in women. Metabolic syndrome was not a mediator in the U-shaped relationship of IGF1 with CVD. Both subjects without the metabolic syndrome and low IGF1 levels (hazard ratio (HR) 1.75, 95% CI 1.12-2.71) and subjects with the metabolic syndrome and high IGF1 levels (HR 2.28, 95% CI 1.21-4.28) demonstrated increased risks of CVD. CONCLUSIONS: In older people, high-normal IGF1 levels are associated with prevalent metabolic syndrome and high triglycerides. Furthermore, this study suggests the presence of different pathomechanisms for both low and high IGF1 levels and incident CVD.

Thyroid function and the metabolic syndrome in older persons: a population-based study.

BACKGROUND: Studies suggest an association between a high TSH and (individual components of) the metabolic syndrome. Only a few studies have been performed in the general older population. OBJECTIVE: This study investigates the association between serum TSH and the metabolic syndrome in a representative sample of older persons in The Netherlands. DESIGN AND PATIENTS: Data of the Longitudinal Aging Study Amsterdam were used, which is an ongoing cohort study in a representative sample of Dutch older persons. A total of 1187 subjects (590 men and 597 women) between the ages of 65 and 88 years participated in the study. MEASUREMENTS: Metabolic syndrome (US National Cholesterol Education Program definition) and its individual components were assessed, as well as serum TSH levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 34.2%. The mean serum TSH was 1.9 mU/l. Subjects in the upper quartile with a serum TSH level above 2.28 mU/l (odds ratio (OR)=1.68; 95% confidence interval (CI) 1.19-2.37) had a significantly increased prevalence of metabolic syndrome compared with subjects in the lowest quartile with a serum TSH below 1.04 mU/l. After adjustment for confounders, age, sex, alcohol use, total physical activity, and smoking, the OR was 1.62 (95% CI 1.15-2.32). CONCLUSIONS: Subjects with a serum TSH in the upper quartile have a higher prevalence of metabolic syndrome as compared with subjects with a serum TSH in the lowest quartile.

Whipple's disease presenting with neurological symptoms in an immunosuppressed patient.

We report an unusual case of Whipple's disease, which remained undiagnosed for several years in a patient being treated with immunosuppressive therapy for many years. The patient presented with a purpuric rash, neurological symptoms, lymphadenopathy and gastrointestinal symptoms. The diagnosis was made by endoscopic biopsy of the duodenum with periodic acid Schiff staining, as well as PCR testing on blood and cerebrospinal fluid. The patient was successfully treated with intravenous ceftriaxone, followed by oral co-trimoxazole for 1 year.